Abstract: TH-PO571

Activation of CD8+ T-Cells Inhibits Cyst Growth in a Murine Model of ADPKD

Session Information

Category: Genetic Diseases of the Kidney

  • 801 Cystic Kidney Diseases

Authors

  • Kleczko, Emily K., University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States
  • Marsh, Kenneth H., University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States
  • Clambey, Eric T., University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States
  • Furgeson, Seth B., University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States
  • Gitomer, Berenice Y., University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States
  • Chonchol, Michel, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States
  • Nemenoff, Raphael A., University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States
  • Hopp, Katharina, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States
Background

Phenotypic heterogeneity observed in Autosomal Dominant Polycystic Kidney Disease (ADPKD) cannot be explained solely by genic effects. As in other disorders, changes in the microenvironment likely contribute to disease variability. In ADPKD, the role of the adaptive immune system, a critical microenvironmental component, is largely unknown. The goal of this study was to determine the function of T-cells in ADPKD progression.

Methods

Using flow cytometry, immunofluorescence, qPCR, histopathology, and antibody depletion, we evaluated the role of T-cells in the ADPKD Pkd1 p.R3277C (RC) model. In the C57BL/6 strain this model progresses slowly, while in the BALB/c strain disease advances rapidly.

Results

By flow cytometry, Pkd1RC/RC mice showed an increase in both CD4+ and CD8+ T-cells, correlating with disease severity (fold change RC vs wildtype (WT) (3mo, 9mo), C57BL/6: 1.9, 8.8; BALB/c: 6.0, 12.3). Importantly, by immunofluorescence, even at mild/moderate disease and modest overall increases in T-cell number, the majority of T-cells localized to cysts (Pkd1RC/RC 3mo; C57BL/6: 87.5%; BALB/c: 85.7%). This was associated with increased Cxcl9 and Cxcl10 expression, both implicated in T-cell recruitment (Pkd1RC/RC 3mo (fold change RC vs WT Cxcl9, Cxcl10); C57BL/6: 2.7, 2.8; BALB/c: 6.6, 17.6). We further observed increases in CD44+/CD69+ CD8+ T-cells but not CD4+ T-cells, and noted that WT animals of the more severe strain (BALB/c) have a lower CD8+ to CD4+ T-cell ratio (1:4 vs C57BL/6 1:1), suggesting selective activation of CD8+ T-cells in our model and a potential correlation of CD8+ T-cell numbers to disease severity. In concordance, antibody depletion of CD8+ T-cells from 1-3 months in C57BL/6 Pkd1RC/RC mice versus IgG control significantly increased %kidney weight/body weight (2.3 vs 2.1), average cyst size (18.6 vs 14.2 x103µm2), and %fibrotic area (2.6 vs 1.7). However, cyst number did not change (8.4 vs 8.6 per mm2), indicating that CD8+ T-cells slow cyst progression/fibrosis, but not initiation.

Conclusion

These data indicate that T-cells are upregulated in ADPKD and are specifically recruited to cystic lesions. Further, CD8+ T-cells play a crucial role in attenuating cyst growth, suggesting that therapeutic compounds designed to activate CD8+ T-cells may be promising ADPKD treatment options.

Funding

  • Private Foundation Support